Repetitive and compulsive‐like behaviors lead to cognitive dysfunction in Disc1^{Δ2‐3/Δ2‐3} mice

Abstract

Disrupted-in-schizophrenia 1 (Disc1) is a key molecular driver for the biology of mental diseases. In order to investigate its role in brain function, we previously generated mice lacking exons 2 and 3 of Disc1 on a C57BL/6J genetic background (Disc1 mice), which have a deficiency of the full-length Disc1 protein. In the present study, we examined the role of Disc1 in cognitive function using a touchscreen-based visual discrimination (VD) task in which mice had to discriminate 1 of 2 stimuli simultaneously displayed on the screen and received a liquid reward. Disc1 mice showed impaired performance in the VD task, and this was mainly attributed to the perseverative response being significantly stronger than that in wild-type (WT) mice. Furthermore, the numbers of marbles buried in the marble burying test and nestlets shredded in the nestlet shredding test by Disc1 mice were significantly higher than those by WT mice, suggesting perseverative/compulsive behaviors by Disc1 mice. A treatment with clozapine ameliorated behavioral deficits in the VD and marble burying tasks. c-Fos expression was significantly stronger in the dorsomedial striatum (DMS), but not the dorsolateral striatum (DLS) after the first VD session in Disc1 mice than in WT mice. The treatment of mice that had previously expressed hM3Dq in the DMS with clozapine-N-oxide (CNO) impaired performance in the VD task. These results suggest that cognitive impairments accompanied by perseverative/compulsive behaviors in Disc1 mice are associated with hyperactivity of the DMS.

Overexpression of Astroglial Major Histocompatibility Complex Class I in the Medial Prefrontal Cortex Impairs Visual Discrimination Learning in Mice

“…Tasks were performed using the touchscreen chamber system (Phenosys, Berlin, Germany; Brainscience Idea, Osaka, Japan). The protocol used was described in detail in previous studies [20,30]. Brie y, access to food and water was restricted for 2 hr each day at least 1 week before pretraining in order to provide su cient motivation to perform the tasks, and food and water restrictions were continued until the end of the task.…”

“…Mice were initially subjected to pretraining to gradually shape screen-touching behavior [20,30]. Pretraining consisted of 5 stages (Fig.…”

“…The dorsal striatum is anatomically divided into DMS and DLS. These areas are involved in VD learning [20,23]. These striatal regions receive excitatory inputs from two major sources, the cortex and thalamus, which control contextual, motor, and perceptual decisions [26,34].…”

“…In the present study, we investigated higher brain functions in sH-2D-expressing mice using the VD task to assess the impact of the astrocyte pathology and resulting behavioral changes. The touchscreen-based VD task provides high translational validity to further evaluate neuronal projections for higher-order brain functions in mice [18][19][20][21][22]. Previous studies indicated that the dorsal striatum is important for VD learning [20,23].…”

“…The touchscreen-based VD task provides high translational validity to further evaluate neuronal projections for higher-order brain functions in mice [18][19][20][21][22]. Previous studies indicated that the dorsal striatum is important for VD learning [20,23]. Instrumental action and outcome behaviors are known to depend on the dorsal striatum and its connections with the mPFC [24,25].…”